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POLD1
Final classification
Likely Benign
BS1BP4BP7
POLD1
c.1275C>T
p.Ala425=
synonymous · exon 11
Gene context NCBI Gene ↗ OncoKB ↗

POLD1 encodes the catalytic subunit of DNA polymerase delta, an enzyme that carries both DNA synthesis and proofreading (3' to 5' exonuclease) activities and is essential for accurate DNA replication and repair. Germline mutations in its exonuclease domain cause polyposis and predispose people to colorectal, endometrial, and possibly brain cancers. In cancer, POLD1 defects impair replication fidelity, leading to the accumulation of many mutations (an ultra-mutated phenotype) that may make tumors more responsive to immunotherapy, though somatic POLD1 mutations are rare.

This variant

This synonymous change (p.(Ala425=)) does not alter the POLD1 protein sequence and is classified Likely Benign, so it is not expected to affect the DNA polymerase delta replication/proofreading activity whose defects cause polyposis and colorectal/endometrial cancer predisposition. Its allele frequency of up to ~1.9% in the general population further supports a benign polymorphism rather than a disease-causing POLD1 alteration.

Transcript
NM_002691.4
HGVS · transcript:coding
NM_002691.4:c.1275C>T
GRCh38
chr19:50406214 C>T
GRCh37
chr19:50909471 C>T
Basis No ClinGen VCEP specification or local gene-specific framework exists for POLD1, so generic ACMG/AMP 2015 (PMID:25741868) combination rules were applied. Applied criteria: BS1 (strong), BP4 (supporting), BP7 (supporting). ▾
No ClinGen VCEP specification or local gene-specific framework exists for POLD1, so generic ACMG/AMP 2015 (PMID:25741868) combination rules were applied. Applied criteria: BS1 (strong), BP4 (supporting), BP7 (supporting).
Classification rationale
BS1BP4BP7 Likely Benign
POLD1 c.1275C>T synonymous · exon 11

BS1 (Strong): gnomAD v4.1 allele frequency up to 1.9228% (Ashkenazi Jewish) is far too common for a rare POLD1 cancer-predisposition disorder. BP4 (Supporting): SpliceAI max delta 0.035 predicts no splicing consequence, below the ~0.1 threshold. BP7 (Supporting): synonymous change with no predicted splice-site impact. Under the generic ACMG/AMP 2015 combination rules, BS1 (strong) together with BP4 and BP7 (supporting) supports a Likely Benign classification.

BS1 + BP4 + BP7 → Likely Benign
Gene diagram · NM_002691.4 · variants mapped to exon structure
POLD1 NM_002691.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength Supporting Moderate Strong Very strong
✓
BS1 strong Benign
Met (strong): allele frequency 1.9228% in Ashkenazi Jewish and 1.3787% in African/African American individuals is far too common for a rare cancer-predisposition disorder.
No POLD1 ClinGen VCEP specification or local gene-specific framework was retrieved; generic ACMG/AMP frequency guidance therefore applies.gnomAD v4.1 has 1,949 variant alleles among 1,613,918 alleles (overall AF 0.1208%); the highest frequencies are Ashkenazi Jewish AF 1.9228% (569/29,592; 7 homozygotes) and African/African American AF 1.3787% (1,034/74,998; 5 homozygotes).gnomAD v2.1 corroborates enrichment: Ashkenazi Jewish AF 1.7685% (183/10,348; 2 homozygotes) and African/African American AF 1.3676% (341/24,934).
gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗
✓
BP4 supporting Benign
Met (supporting): SpliceAI max delta 0.035 is well below the ~0.1 threshold for no predicted splicing consequence.
SpliceAI max delta score = 0.035 (DS_AG=0.035, DS_AL=0.001, DS_DG=0.001, DS_DL=0.005) for NM_002691.4:c.1275C>T, well below thresholds associated with splice-altering variants.SpliceAI delta-score interpretation thresholds (0.2 high recall / 0.5 recommended / 0.8 high precision) are from Jaganathan et al. 2019 (Cell), PMID 30661751; the observed score of 0.035 is well below even the lowest of these thresholds, supporting no predicted splicing impact.
spliceai ↗
✓
BP7 supporting review Benign
Met (supporting): SpliceAI max delta 0.035 predicts no splice-site creation or disruption for this synonymous change. Flagged for human review: no nucleotide-level conservation score was available to confirm.
gnomAD VEP annotation: most_severe_consequence = synonymous_variant for this variant, confirming p.(Ala425=) is a silent change.SpliceAI max delta score = 0.035, indicating no predicted disruption of splice donor/acceptor sites or creation of a new splice site.
spliceai ↗
Assessed · not applied · 5 not met · 12 not assessed
Pathogenic
PS2 Not assessed: no de novo observation with parental genotypes or parentage confirmation was available.
PS3 Not assessed: no functional studies of this variant (e.g., polymerase fidelity or splicing assays) were available.
PS4 Not assessed: no case-control or case-series data involving this exact variant were available.
PM2 Not met: gnomAD v4.1 allele frequency 0.1208% (up to 1.9228% in Ashkenazi Jewish) shows the variant is too common to be rare.
PM3 Not assessed: no affected individual carrying this variant opposite a pathogenic POLD1 variant was documented.
PM6 Not assessed: no de novo observation with parental testing was available.
PP1 Not assessed: no informative affected relatives or segregation data were reported.
PP3 Not met: SpliceAI max delta 0.035 shows no predicted splice impact, and no missense predictor applies to a synonymous change.
PP4 Not assessed: no affected-individual phenotype or phenotypic segregation data were provided.
PP5 Not met: ClinVar reports no expert-panel submission for this exact variant.
Benign
BA1 Not met: the highest population allele frequency, 1.9228% in Ashkenazi Jewish, is below the 5% BA1 threshold.
BS2 Not assessed: population databases report homozygotes, but no phenotyped healthy adults confirm benignity.
BS3 Not assessed: no functional assay demonstrating no damaging effect on POLD1 function or splicing was available.
BS4 Not assessed: no informative non-segregation evidence (affected non-carriers or unaffected carriers) was reported.
BP2 Not assessed: no co-occurrence of this variant with a pathogenic POLD1 variant was documented.
BP5 Not assessed: no phenotype or molecular workup documenting an alternate cause was provided.
BP6 Not met: ClinVar reports no expert-panel submission for this exact variant.
N/A · 8 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00120762; MAF= 0.12076%, 1949/1613918 alleles, homozygotes = 12) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0192282; MAF= 1.92282%, 569/29592 alleles, homozygotes = 7); grpmax FAF= 0.0130893.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00209797; MAF= 0.20980%, 593/282654 alleles, homozygotes = 2) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0176846; MAF= 1.76846%, 183/10348 alleles, homozygotes = 2); grpmax FAF= 0.0121365.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.001738752445120626, 32/18404 alleles, homozygotes = 1).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.12% · 1949 / 1,613,918
12 hom · FAF 1.3%
Ashkenazi Jewish
569 / 29,592
1.9%
7 hom
African/African American
1034 / 74,998
1.4%
5 hom
Remaining individuals
156 / 62,502
0.25%
Middle Eastern
6 / 6,062
0.099%
Admixed American
47 / 60,010
0.078%
European (non-Finnish)
133 / 1,179,912
0.011%
South Asian
4 / 91,076
0.0044%
+ 3 not observed (European (Finnish), Amish, East Asian)
gnomAD v2.1
0.21% · 593 / 282,654
2 hom · FAF 1.2%
Ashkenazi Jewish
183 / 10,348
1.8%
2 hom
African/African American
341 / 24,934
1.4%
Remaining individuals
14 / 7,218
0.19%
Admixed American
20 / 35,412
0.056%
European (non-Finnish)
33 / 129,098
0.026%
South Asian
2 / 30,610
0.0065%
+ 2 not observed (East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.17% · 32 / 18,404
1 hom · FAF 0.99%
African/African American
16 / 1,018
1.6%
1 hom
Ashkenazi Jewish
7 / 832
0.84%
Remaining individuals
3 / 1,138
0.26%
Latino/Admixed American
2 / 838
0.24%
European (non-Finnish)
4 / 11,726
0.034%
+ 4 not observed (East Asian, European (Finnish), Middle Eastern, South Asian)
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Benign (16 clinical laboratories) and as Likely benign (2 clinical laboratories). (ClinVarID = 220965)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV70957061, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 4 PMIDs not cited in assessment
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR